Androgenic hormones are thought to modulate immune system function and to influence the course of autoimmune diseases but mechanisms by which such effects might be mediated are unknown. We propose to investigate the effects of androgens on specific aspects of T cell homeostasis in older men undergoing therapeutic manipulation of androgen levels. We will test the hypothesis that androgens modulate the age-related diminution in thymic output of T cells. Flow cytometric techniques will be used to assess the impact of androgen deprivation therapy on the quantities of na[unreadable]ve helper T cells in the circulation of older men. Quantitative real time polymerase chain reaction techniques will be used to assess the abundance of T cell receptor excision circles (TRECs), a marker of cells recently emigrated from the thymus, in the circulation of men before and after androgen replacement or androgen deprivation therapies. We will test the hypothesis that androgens alter the course of proliferative senescence of peripheral T cells. Flow cytometric techniques will be used to quantitate senescent T cells in both CD4+ and CD8+ subsets from men before and after androgen replacement or androgen deprivation treatment. Measurements of average telomere length and telomerase activity will be made on flow sorted na[unreadable]ve and senescent T cell populations from men before and after androgen replacement or androgen deprivation treatment. Experiments in vitro will explore whether androgens regulate telomerase activity in peripheral T cells, whether androgens regulate the telomerase reverse transcriptase gene (hTERT) in these cells at the transcriptional level, or whether androgens regulate post-translational modifications of hTERT that activate the protein These studies will expand our knowledge of interactions between the endocrine and immune systems and their alterations in aging. The findings will help us understand whether declining testicular function in older men or therapies to alter circulating androgen levels might contribute to increased risk for infectious, neoplastic and autoimmune diseases. [unreadable] [unreadable] [unreadable]